Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis

Abstract

The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.

Translational potential of human brain organoids

“…This landmark paper established a novel experimental paradigm for generating tissue organoids. Subsequent studies worldwide confirmed the generalizability of such approach to human stem cells, and produced organoids of a variety of organ types including colon,11 intestine,12 prostate,13, 14 fallopian tube,15 stomach,16 liver,17, 18 kidney,19 lung,20 and brain 8…”

Modeling infectious diseases and host-microbe interactions in gastrointestinal organoids

“…The virus preferentially infected and replicated in neural progenitors, induced cell death and decreased proliferation, leading to reduced neuronal cell layers and thus phenocopying the microencephaly caused by the virus in human fetuses (Dang et al, 2016;Garcez et al, 2016;Tang et al, 2016). Other organoids such as lung (Dye et al, 2015;Huang et al, 2013), liver Takebe et al, 2013), kidney (Takasato et al, 2015) and fallopian tube organoids (Kessler et al, 2015) may represent ideal models for infections of the respective tissues, such as respiratory virus, malaria parasite, biofilm-producing E. coli or Chlamydia infection, respectively. Future studies will use the unique features of organoids, such as the presence of specific cell types, to better understand infectious and inflammatory diseases.…”

3D Miniaturization of Human Organs for Drug Discovery

“…On this basis, his group has generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. [142] Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. Transcription profiles of kidney organoids closely mimicked first trimester human kidneys.…”